Efficacy and Financial Toxicity

Whitney Lewis

Liz, it seems like there’s been so much change in the lung cancer landscape over the last couple of years! I feel there is a new approval for something related to lung cancer every other month. What are some of the new drugs or regimens you’ve seen and are most excited about?

Elizabeth Waxman

Well Whitney, you’re right about that. It’s becoming a lot to keep up with! We’ve seen older drugs such as alectinib and osimertinib find their way into earlier lines of therapy, like adjuvant therapy after surgical resection or chemoradiation.¹ There are some novel bispecific antibodies such as zenocutuzumab for the rare patient with NRG1 fusions² and there is also a new ALK inhibitor, ensartinib.³ We’ve also seen repotrectinib receive FDA approval for NTRK and ROS1 fusions,⁴ and lorlatinib has made its way to the front-line setting for ALK fusions.⁵ We’ve seen combinations of older medications such as amivantamab plus chemotherapy and osimertinib plus chemotherapy for certain EGFR mutations,^6,7 as well as a novel combination of amivantamab and a new EGFR TKI lazertinib.⁸ There are other compounds under breakthrough designation and priority review so I think changes are going to keep coming our way!

Whitney Lewis

It seems like most updates are taking place in patients with targetable mutations. It’s so rewarding when we find those in the pathology reports. I wish we were moving the needle as much for patients without targetable alterations but unlocking KRAS was incredible for so many patients. Liz, do you find the pathology reports overall easy to read and interpret? It seems like for some mutations, for example EGFR, it can be rather complicated now that there are so many mutations with an accessible therapy.

Elizabeth Waxman

Yes, Whitney, I think the pathology reports are easy to read and interpret. And I think it’s important to be succinct when explaining the reports to patients. I’m trying to remember what the approvals are for EGFR exon 20 insertion mutations.

Whitney Lewis

This has been such a dynamic space the last few years! We’ve seen FDA approval for mobocertinib for second-line treatment and then have its application withdrawn from the US market shortly thereafter.⁹ We saw amivantamab receive FDA approval in the second-line after chemotherapy,⁶ and in my opinion, what has been the most impactful is a recent front-line approval with chemotherapy for this patient population based on the PAPILLON trial. PAPILLON was a randomized phase 3 trial comparing chemotherapy to chemo plus amivantamab. The combination essentially doubled progression-free survival from 6-7 months to almost 12 months and also had a better response rate of ~75% compared to ~50%, and perhaps most importantly the response was durable at about 10 months on the combination arm compared to just 4 months on chemotherapy alone.⁶ 

Liz, what are your thoughts on some of the new approvals in the classical EGFR mutation space? It seems like there’s a lot of nuance to selecting regimens for this group of patients now than there ever has been.

Elizabeth Waxman

There are so many options now for frontline metastatic EGFR mutated NSCLC. It’s been great to have so many to choose from and really discuss with my team which patients may benefit from treatment intensification. One of the newer options for this is from the FLAURA2 randomized trial comparing the standard of care osimertinib to osimertinib plus chemotherapy. The addition of chemotherapy to osimertinib resulted in a slight benefit in response rates of about 7-9%, and about a 9-month benefit in progression free survival.^10,11 Data are still too immature to prove a survival benefit but are trending in the right direction at the last interim analysis, showing a median OS of the combination arm was not reached vs. ~36 months.

Whitney Lewis

Liz, thank you so much for that refresher. These data are so exciting when we think back to the pre-TKI days or even with the first- and second-generation EGFR inhibitors. We haven’t adopted this fully for every new patient yet since the OS data is not yet mature, and when we think about an EGFR patient they may still be younger and not wanting to be on chemotherapy yet. Are there any specific populations you’re offering the combination therapy arm to?

Elizabeth Waxman

We’re also waiting to see if upfront chemo plus osimertinib is better than adding chemotherapy to osimertinib at the time of progression before we make it the standard for everyone. However, there are some groups of patients we advocate therapy intensification for such as those with a high disease or symptom burden as well as those with baseline brain metastases. One of the most compelling findings in FLAURA2 was the delay in time to progression, about 11 months, so almost a year, for patients with baseline CNS metastases compared to those without.¹¹ Whitney, I think there was also a new approval for amivantamab plus lazertinib in this space as well recently, right? What do you think about that regimen and who are you offering it to?

Whitney Lewis

Yes! There is a new additional option for front-line EGFR patients with classical mutations in L858R and del19 with lazertinib, another third-generation EGFR TKI with excellent CNS penetration and perhaps less cardiotoxicity, and amivantamab which is a bispecific antibody for EGFR and MET. To me this is an exciting combination because it is a way to intensify therapy from a third-generation TKI alone without the addition of chemotherapy, which many patients still try to avoid as long as possible. This combination aims to circumvent some of the most common resistance mechanisms to EGFR inhibition, namely MET amplification. The MARIPOSA trial randomized patients to osimertinib or amivantamab plus lazertinib in the frontline setting. Response rates were virtually identical, but there was ~7-month benefit in PFS for the combination arm over osimertinib alone, 24 vs. 17 months, and a 9-month benefit in duration of response, similar to the benefits seen with FLAURA2, and patients benefitted regardless of the presence of baseline CNS metastases.¹²

Elizabeth Waxman

You know one thing we don’t talk about enough is the financial implications of these treatments. It’s such a blessing to have all of these modern treatments available for patients and incredible to know that the average patient may be on therapy for months to years. However, the cost of treatments can really add up over time and become an undue hardship on patients, especially younger patients who are still dependent on working full-time jobs for health-care benefits. Do you have some estimated costs of these treatments?

Whitney Lewis

Liz, financial implications are so often glossed but can be so impactful in a patient’s day-to-day life and stress. I can’t speak to average facility costs, but in terms of straight drug cost, osimertinib is about $700 per tablet. I’ve seen the drug approved anywhere from a $0 copay to paying 10-20% of the cost. And I try to remind patients that 10-20% of a lot can still be a lot, like thousands of dollars per month in copay fees. While there is a copay assistance program, the requirements for that have tightened up in recent years and we are starting to see more patients with financial difficulties. 

Now that pemetrexed is generic (and carboplatin has been for many years), the actual cost of chemotherapy may be only a couple hundred dollars, but this does not account for pharmacy prep, nursing administration, and other facility fees. Keeping in mind this treatment is given every 3 weeks, it can still contribute substantially to a patient’s financial burden despite the relatively low cost of the actual chemotherapy drug. Amivantamab on the other hand, assuming a 1400 mg dose, has an actual drug cost of $5000 per month, plus all of the fees discussed with chemotherapy. Lazertinib itself is similar in cost to osimertinib. Due to this being a newer therapy, it’s possible there is more manufacturer assistance in place for this regimen, but I don’t have any direct experience yet. 

Liz, are you able to comment on the changes you’ve seen so far with patient cost for these medications?

Elizabeth Waxman

You’re right, the cost of targeted therapies can be prohibitive. One important point is that when a targeted therapy is prescribed, the oncology team will need to do a prior authorization, which is a questionnaire from the patient’s insurance company that asks for demographic information and the indication for this treatment. The insurance company usually requests mutation testing results and a physician’s clinic note. The point is that even though the patient will be treated with a targeted therapy, it can take a few days before the patient actually starts treatment.

The patients can stay on targeted treatment as long as it’s effective. Targeted therapy lends a chronicity to lung cancer as the patient doesn’t have to come in for clinic evaluation and treatment every 3 weeks as they did with chemotherapy. The patient doesn’t necessarily need to take time off from their work for treatment. Targeted therapy gives patients a chance at a normal life.

Whitney Lewis

Financial toxicity is something that isn’t always top of mind when we talk about cancer care, but it’s very important to address it.

Whitney Lewis

I agree, Whitney, so I’m glad we got a chance to talk about that and so much more today.

Whitney Lewis

I am too.